GOCADAN (Genetics of Coronary Artery Disease in Alaska Natives) is a study of the relative contributions of genetic and environmental factors to cardiovascular disease (CVD) in Eskimos in the Norton Sound region of Alaska. CVD and its risk factors are increasing rapidly in Alaska Eskimos as their lifestyle and traditional diets become westernized. During Phase I, we have collected family data on 1214 GOCADAN participants. Initial analyses of the Phenotypic data show a high prevalence of atherosclerotic plaque and self-reported CVD, in the presence of favorable lipoprotein, blood pressure, and insulin resistance profiles, but high levels of smoking, pathogen burden, and C-reactive protein (CRP). Our genetic analyses show that key CVD risk factors have significant heritabilities, and have detected pleiotropic effects on CVD- related phenotypes. Our initial genome scan has identified promising quantitative trait loci (QTLs) for CVD-related phenotypes including a QTL for diabetes on chromosome 2q, a QTL for lipid levels on chromosome 19, and a QTL for blood pressure phenotypes on chromosome 2p. Because the data collected so far raise many unanswered questions concerning the relatives contribution of genes and environment to the high prevalence of atherosclerotic plaque and CVD in this population, we propose to continue this study with the following specific aims: 1) examine positional candidate genes in proximity to CVD risk factor QTLs using Bayesian quantitative trait nucleotide (QTN) analysis to identify genetic variation that accounts for our linkage signals, 2) continue genome-wide linkage and other quantitative genetic analyses of CVD-related phenotypes collected in Phase I and II examinations, including new phenotypes collected in Phase II, 3) assess the genetic contribution to changes in CVD-related phenotypes between Phase I (baseline) and Phase II (follow-up) examinations, and 4) continue to serve as the Data Coordinating Center and as a resource for Norton Sound Health Corporation, MedStar Research Institute and Cornell Medical Center in the Phase II re-examination of family members. This study should prove invaluable in the identification of genetic factor that interact with lifestyle and diet to increase susceptibility to CVD in both Alaskan Eskimos and the general population. GOCADAN will lead to valuable therapeutic and prevention strategies for Eskimos and other populations, where the epidemics of obesity, diabetes, and CVD are increasing rapidly.